The present invention is concerned with flurbiprofen-containing medicaments comprising a mixture of flurbiprofen enantiomers, present as previously separated compounds, as active material, as well as with the preparation thereof, and with the use of said medicaments as rapidly or controlled inflowing, as well as acceleratedly-acting, analgesics and antiphlogistics and/or antipyretics in the case of pain and/or inflammations and/or fever in humans and animals.
Flurbiprofen (2-(2-fluoro-4-biphenylyl)propionic acid), which has the following structure: ##STR1## is a medicament which has been known for a long time (see Federal Republic of Germany Patent Specification DE-C-15 18 528) and which is widely used because of its anti-inflammatory, antipyretic and analgesic action (see Martindale, The Extra Pharmacopoeia, 20th edn., p. 18, 1989).
In the case of chemical synthesis, flurbiprofen is normally obtained as a racemate and is also used in this form in various medicaments. Furthermore, it is known that this compound, especially in the case of long-term treatment of painful and inflammatory processes, displays undesirable side effects, especially gastrointestinal irritations or damage, such as ulcers, perforations and the like (see Martindale (loc. cit.)).
It is known that, in the case of many pharmacologically-active 2-arylpropionic acid derivatives, the biological in vitro activity (prostaglandin synthesis inhibition, thrombocyte aggregation inhibition) of one of the enantiomers is greater than that of the other one, whereas the side effects, in many cases, are to be attributed to both enantiomers or even to the pharmacologically less active enantiomer. Thus, in Federal Republic of Germany Patent Specification No. DE-A-29 09 794 a process is suggested to increase the proportion of the pharmacologically-active enantiomer in comparison with the racemate. For this purpose, a solution which contains the racemic active material or an active material already partly enriched in one of the enantiomers is reacted in a non-polar solvent with an optically active alkylamine, preferably with .alpha.-phenylethylamine, to give a diastereomeric salt mixture, the amount of solvent thereby not being sufficient in order to dissolve this salt completely. Therefore, the sparingly soluble component is enriched in the precipitate. Depending upon the optically-active base used and the solvent employed, in this way, inter alia, there can also be prepared the two optically-active enantiomers of flurbiprofen. However, the pharmacological effectiveness of the enantiomers is not given in this literature reference.
From A. Sunshine et al., Clin. Pharmacol Ther., 41 (2), 162/1987, it is known to use S(+)-flurbiprofen as an analgesic in the case of post-episiotomy pain. In a double blind study, it was thereby found that S(+)-flurbiprofen, compared with the racemate, is already more effective at half dosage so that it was assumed that the enantiomer is solely responsible for the analgesic action.
Surprisingly, we have now found that, contrary to this knowledge, not S(+)-flurbiprofen but also R(-)-flurbiprofen is outstandingly analgesically effective in recognized pain models. This unexpected result was verified by investigations in two animal models (mouse and rat). Not only in the cramp pain test in mice but also in the interleukin 1-induced pain test in rats, the R-enantiomer, as can be seen from FIGS. 1 and 2 of the accompanying drawings, is equal or even more effective by about one third to a half. Otherwise than in the case of other known 2-arylpropionic acid derivatives, these results are clearly to be assigned to the enantiomers, since not only after R(-) but also after S(+)-flurbiprofen administration, no or only a very small inversion takes place.
Furthermore, contrary to the published state of knowledge (v. supra), S(+)-flurbiprofen in the case of administration after episiotomy is preferably effective antiphlogistically and not preferably analgesically. This further surprising test result was tested on two inflammation models selected independently of one another. Thus, on macrophages (peritoneum of the mouse), it was shown that S(+)-flurbiprofen inhibits the liberation of prostaglandin more markedly than the R(-)-form.
In the case of carrageenin paw oedema in the rat, S(+)-flurbiprofen is also superior in its inflammation-inhibiting action to the R(-)-form, as is demonstrated in FIGS. 3 and 4 of the accompanying drawings. In accordance with the present thinking as seen from FIG. 7, we have found that only S(+)-flurbiprofen caused damage of the gastro-intenstinal mucosa of rats.
According to the present state of knowledge of the mechanism of action of medicaments in the case of successful combating of pain of differing genesis, differention must be made as follows.
In the case of analgesics, the rapid commencement of action is an outstanding factor. It is a prerequisite of this that, in the case of oral, topical or other non-parenteral forms of administration, an accelerated liberation initially takes place as well as a sufficiently good bioavailability of the active material(s). Furthermore, such analgesics block because the conduction from the awareness of pain takes place via a conduction system ascending from the periphery to the central nervous system (CNS), the control mechanisms being present on different planes of the CNS on which participate receptors with chiral structures.
Furthermore, it is assumed that the inhibition of the prostaglandin biosynthesis acts a a common feature of the action mechanism in the case of analgesics and antiphlogistics (see J. R. Vane, Nature, p. 231 et seq., 1971; G. A. Higgs, Brit. J. Clin. Pharmacol., 10, 233 et seq. 1980). Thus, this action is to be understood as a connecting member between the alleviation of pain and the inhibition of inflammation. However, all effects cannot be solely explained with this mechanism. Thus, in the case of acidic analgesics and/or antiphlogistics, such as flurbiprofen, neuro-physiological effects are also probable as a result of the incorporation of such active materials in the cell membranes.
Prostaglandins participate in the initiation of the classical symptoms in the case of inflammations, such as reddening, swelling, oedema and thus pain. Such inflammatory changes can be reduced by means of inflammation-inhibiting active materials, the patient thereby simultaneously experiencing an amelioration of pain. At present, this is the main field of use of the non-steroidal inflammation inhibitors (antiphlogistics). Of the antiphlogistics, only a few representatives can be employed for differentiated or pure treatment of pain. These include, for example, indomethacine, naproxen and ibuprofen, which are also analgesically effective in the case of spasms of the smooth musculature. By far the greater number of the non-steroidal antiphlogistics is excluded from anti-rheumatic therapy because of insufficient analgesic action and because of a number of undesirable effects.